Schizophrenia(SCZ)isachronic,severeanddisablingmentalillnessthataffects1%ofthepopulation,yethas no effective treatment. Antipsychotic medications can interrupt positive symptoms such as hallucinations in a subsetofindividuals,buthavelittleimpactonnegative(socialwithdrawn)orcognitivesymptoms.Tremendous progressinhumangeneticsinthepastfewyearshasrevealedpolygenicriskfactorsunderlyingschizophrenia. Ourbestchancetodevelopthenextgenerationtherapeuticsforschizophreniareliesonourabilitytodiscover and validate novel biological risk factors implicated by the emerging SCZ genetics. CACNA1I is a risk gene identifiedbyGWAS,andencodethe?1functionalcoreoftheCaV3.3voltage-gatedcalciumchannels.Emerging evidencesconnectthefunctionofCaV3.3withafewclinicalobservationsintheschizophreniapatientsincluding sleep spindle deficits. We hypothesize that impaired CaV3.3 plays a role in mediating SCZ risk, and it representsapotentialnoveltargetforschizophrenia.Here,weproposetoutilizeaprimaryHTSscreen and a cascade of secondary physiological and cellular assays to identify positive and negative modulatorsthatregulateCaV3.3functionwithhighspecificity.BycombiningHTS,appropriatesecondary screens,alongwithsubsequentmedicinalchemistryoptimization,thismultidisciplinaryeffortisexpectedtoyield apanelofincisivechemicalprobestodissecttheexpandingbiologicalfunctionofCaV3.3inneurobiologyand schizophreniadiseasemechanism. 1